Triethylamine → (4R)-3-Methyl-N-[(1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine

HRID 1261703Notes

Reaction equation

HRID 1261703 reaction equation
Cl.Cl.[O:3]1[CH2:7][CH2:6][C@H:5]([C@:8]2([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]2)[CH2:4]1.[CH3:32][CH:33]1[C:38](=O)[CH2:37][CH2:36][O:35][CH2:34]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:32][CH:33]1[C@H:38]([NH:13][C@@H:10]2[CH2:11][CH2:12][C@:8]([C@H:5]3[CH2:6][CH2:7][O:3][CH2:4]3)([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH2:20][CH2:21]3)=[O:15])[CH2:9]2)[CH2:37][CH2:36][O:35][CH2:34]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 141709263-Methyloxan-4-oneHCID 68596876(1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride

Product 1

HCID 68596739(4R)-3-Methyl-N-[(1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amineYield 12%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (73.8 mg, 0.152 mmol), 3-methyltetrahydro-4H-pyran-4-one (52.1 mg, 0.456 mmol) and triethylamine (0.0848 mL, 0.608 mmol) in dry methylene chloride (4.1 mL) was added sodium triacetoxyborohydride (96.7 mg, 0.456 mmol). After being stirred at room temperature under N2, the reaction was quenched with aqueous NaHCO3 and diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The organics were combined, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (Combi-Flash system, 0 to 40% MeOH in EtOAc, gradient, 12 gram column) to provide the desired product (9.1 mg, 12%). MS calculated for C26H37F3N4O3; (M+H) 511.3; found 511.3.

Workup

  1. customthe reaction was quenched with aqueous NaHCO3
  2. additiondiluted with CH2Cl2
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with CH2Cl2 three times
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. custompurified by silica gel chromatography (Combi-Flash system, 0 to 40% MeOH in EtOAc, gradient, 12 gram column)

Sources & evidence

ORD record
ord-d1f38a282fe4446698c1244e2875b03f
Source dataset
uspto-grants-2013_06
Patent number
US08470827B2

Reaction notes

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